Kinases are attractive drug targets due to their key role in various cellular activities including proliferation, survival, apoptosis, metabolism and differentiation. Commonly small molecule inhibitors compete directly with ATP and form vital hydrogen bonding interactions with the kinase hinge region. In Phosphoinositide 3-kinase (PI3K) inhibitors this interaction is often made via an aryl morpholine hinge binding moiety (1). Co-planarity between these two rings is a requirement for activity and thus ring systems which adopt orthogonal conformations such as aryl tetrahydropyran (2) are ineffective as morpholine isosteres, whereas unsaturated systems (3) are often considered undesirable. We have identified 3-oxabicyclo[4.1.0]heptane (4) as the first example of a saturated, carbon linked hinge binding moiety for the PI3K family of kinases. Cyclopropyl carbon-carbon bonds are known to form stabilising interactions with adjacent π-systems when in a favourable orientation and DFT conformational studies have suggested low energy co-planar conformations for aryl 3-oxabicyclo[4.1.0]heptane systems. We have subsequently synthesised a series of tool compounds to aid investigation into the application and limitation of this potential morpholine isostere. We have utilised; predictive DFT calculations, X-ray crystallography (figure 1), NMR studies and biological evaluation of these tool compounds to comprehensively investigate the conformational preference of 3-oxabicyclo[4.1.0]heptane when attached to a range of 6-membered heterocyclic rings. We will report our findings which suggest a subtle stereoelectronic balance to conformation with a significant impact for applicability of 3-oxabicyclo[4.1.0]heptane as a general morpholine isostere.

Investigating the scope of 3-oxabicyclo[4.1.0]heptane as a bioisostere for morpholine in kinase hinge binding fragments

256th National Meeting (2018)

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